Morbidity and mortality of severely burned patients still remain unacceptably high. Recent evidence indicates that hypermetabolism, a hallmark of severely burned patients, is a major contributor to these detrimental outcomes. Despite the widely recognized importance and complexity of the post-burn hypermetabolic response, the underlying mechanisms by which a thermal injury induces and sustains hypermetabolism for years after the injury are not well defined. Over the previous funding period, we identified that the endoplasmic reticulum (ER) stress response is profoundly affected by a severe burn. We further investigated the role of ER stress during the post-burn response and found that ER stress is associated with substantial metabolic alterations including insulin resistance (IR), lipolysis, cell death, inflammatory responses, and ultimately organ dysfunction. Our novel preliminary data indicate that augmenting ER stress greatly increases post-burn mortality. Thus, we hypothesize that the ER stress response is one of the central mediators of post-burn morbidity and mortality. As such, we aim to test the mechanistic basis by which the ER stress response is activated and leads to significantly greater morbidity. Specifically, the goal of this competitive renewal is to investigate the precise molecular mechanisms by which ER stress leads to increased morbidity and mortality. Based on extensive preliminary data we propose to determine the effects of augmented ER stress on mitochondrial function, calcium signaling via IP3R activity, and mTOR signaling at mitochondria-associated ER membranes (Aim 1).
In Aim 2 we propose to test the novel hypothesis that unfolded proteins that accumulate during ER stress are Danger Associated Molecular Pattern (DAMP) molecules.
Aim 3 will focus on our recent discovery that burn-induced ER stress causes profound activation of the hepatic NLRP3 inflammasome. We will test the hypothesis that released DAMPs, including ER stress-induced protein aggregates, can activate the NLRP3 inflammasome in the liver to stimulate IL- production and systemic inflammation contributing to post-burn multi-organ dysfunction. This project is highly innovative in that to-date the cellular and molecular mechanisms underlying the post-burn hypermetabolic response have not been identified and despite improved clinical care, the detrimental sequelae of this response leads to substantial morbidity and mortality after burn. The relevance of this project is that we will explore novel mechanisms that can lead to the development of new treatment avenues for burn patients or other patients in a hypermetabolic state.

Public Health Relevance

A key and novel aspect of this study is the recent discovery that augmented ER stress, which is linked to hypermetabolism, causes increased mortality after burn. The aim of our research is to identify the molecular mechanisms by which ER stress decreases survival and develop novel strategies that will improve outcomes after burn injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM087285-07
Application #
9330864
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2010-09-30
Project End
2019-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Sunnybrook Research Institute
Department
Type
DUNS #
246840065
City
Toronto
State
ON
Country
Canada
Zip Code
M4 3M5
Chen, Peter; Stanojcic, Mile; Jeschke, Marc G (2018) Septic predictor index: A novel platform to identify thermally injured patients susceptible to sepsis. Surgery 163:409-414
Amini-Nik, Saeid; Sadri, Ali-Reza; Diao, Li et al. (2018) Accumulation of myeloid lineage cells is mapping out liver fibrosis post injury: a targetable lesion using Ketanserin. Exp Mol Med 50:81
Diao, Li; Auger, Christopher; Konoeda, Hisato et al. (2018) Hepatic steatosis associated with decreased ?-oxidation and mitochondrial function contributes to cell damage in obese mice after thermal injury. Cell Death Dis 9:530
Yan, Jinhui; Hill, William F; Rehou, Sarah et al. (2018) Sepsis criteria versus clinical diagnosis of sepsis in burn patients: A validation of current sepsis scores. Surgery 164:1241-1245
Dolp, Reinhard; Rehou, Sarah; McCann, Matthew R et al. (2018) Contributors to the length-of-stay trajectory in burn-injured patients. Burns 44:2011-2017
Amini-Nik, Saeid; Yousuf, Yusef; Jeschke, Marc G (2018) Scar management in burn injuries using drug delivery and molecular signaling: Current treatments and future directions. Adv Drug Deliv Rev 123:135-154
Stanojcic, Mile; Abdullahi, Abdikarim; Rehou, Sarah et al. (2018) Pathophysiological Response to Burn Injury in Adults. Ann Surg 267:576-584
Bakhtyar, Nazihah; Jeschke, Marc G; Herer, Elaine et al. (2018) Exosomes from acellular Wharton's jelly of the human umbilical cord promotes skin wound healing. Stem Cell Res Ther 9:193
Jeschke, Marc G; Shahrokhi, Shahriar; Finnerty, Celeste C et al. (2018) Wound Coverage Technologies in Burn Care: Established Techniques. J Burn Care Res 39:313-318
Auger, Christopher; Sivayoganathan, Thibacg; Abdullahi, Abdikarim et al. (2018) Metformin adapts its cellular effects to bioenergetic status in a model of metabolic dysfunction. Sci Rep 8:5646

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